Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia – a HARMONY study

Journal article

NPM1-mutated (NPM1-mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult NPM1-mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in FLT3-ITD, DNMT3A, IDH1/IDH2, and TET2 genes, was applied to a training cohort of NPM1-mut AML patients included in clinical trials (n = 1001), an internal validation cohort more representative of real-world settings (n = 762), and an external validation cohort enrolled in UK-NCRI trials (n = 585). The HARMONY classification considered 51.8% of the NPM1-mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively; p < 0.001), thereby reclassifying 42.7% of NPM1-mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the NPM1-mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult NPM1-mut AML with potential clinical impact on allo-HSCT decision-making.

Authors: Hernández-Sánchez, A; Villaverde Ramiro, Á; Sträng, E; Turki, AT; Abáigar, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature [academic journals on nature.com]
• Journal: Leukemia
• Volume: 40
• Issue: 2
• Pages: 418-428
• Publication date: 2026-01-14
• Acceptance date: 2025-12-12
• DOI: 10.1038/s41375-025-02851-9
• EISSN: 1476-5551
• ISSN: 0887-6924
• Language: English
• Keywords: NPM1; Myeloid leukemia; Cohort; Transplantation; Clinical trial; Hematopoietic stem cell transplantation; Cohort study; Adverse effect; Myeloid